XII Michelangelo Foundation Seminar

XII Michelangelo Foundation Seminar The opportunity of the neoadjuvant approach L. Gianni, Milan, I

XII Michelangelo Foundation Seminar Milano, October 12, 2012 The opportunity of the neoadjuvant approach Department of Medical Oncology San Raffaele Scientific Institute Milan - Italy Luca Gianni

NEJM, June 28, 2012 Vol. 366 No. 26:2438-2441

Neoadjuvant treatment as ideal tool to study/predict therapeutic benefit Before During After Diagnosis PST Surgery Follow-up Core biopsy (Core biopsy) Surgical biopsy Assessment using IHC, FISH, DNA arrays, RNA arrays, proteomics Verification Predictive biomarkers (Response biomarkers) Resistance biomarkers Kaufmann M, et al. J Clin Oncol 2003;21:2600 8

The Opportunities Dealing with tumor heterogeneity Quick ranking of new drugs/new combinations Exploring features of metastatic stage Linking short-term effects (response, surrogate marker) and longterm efficacy (DFS, PFS, RFS, OS) Moving away from large adjuvant trials?

Molecular heterogeneity reveals specific intrinsic subtypes of breast cancer Unsupervised analysis of global gene expression patterns unveiled distinct and robust molecular subtypes of breast cancer (Class Discovery) Sørlie T et al PNAS 2001

Matching the drug and the tumor characteristics: Intrinsic subtypes, prognosis and pcr PROGNOSIS RESPONSE TO NEOADJUVANT CHEMOTHERAPY Molecular classification pcr Luminal A/B subtype 2/30 7% Normal breast like 0/10 0% HER2 + 9/20 45% Basal subtype 10/22 45% Fan C et al NEJM 2006 Rouzier R et al Clin Cancer Res 2005

Triple Negative Breast Cancers primary TNBCs are still treated as if they were a single disease entity, yet it is clear they do not behave as a single entity in response to current therapies L. Carey et al, Nat Rev Clin Oncol 2010

A novel molecular stratification of breast cancer derived from the impact of somatic Copy Number Aberrations (CNAs) on the transcriptome Nature, 2012

Target-therapies under clinical development: many opportunities PhRMA Report 2009, Medicines in development for cancer

Target-therapies under clinical development: (too) many opportunities PhRMA Report 2012, Medicines in development for cancer

Neoadjuvant studies to rank new HER2 therapies: the NeoSphere trial Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumours >2cm (N=417) TH (n=107) Docetaxel (75 100 mg/m 2 ) Herceptin (8 6 mg/kg) THP (n=107) Docetaxel (75 100 mg/m 2 ) Herceptin (8 6mg/kg) Pertuzumab (840 420 mg) HP (n=107) Herceptin (8 6mg/kg) Pertuzumab (840 420 mg) TP (n=96) Docetaxel (75 100 mg/m 2 ) Pertuzumab (840 420 mg) S U R G E R Y Phase II design Primary End Point: comparison of pcr rates TH v. THP TH v. HP THP v. TP Secondary End Points: Clinical response DFS Breast Conservation rate Biomarker evaluation Study dosing: q3w x 4 BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=t2 3, N2 3, M0 or T4a c, any N, M0; operable=t2 3, N0 1, M0; inflammatory = T4d, any N, M0

NeoSphere: Superior pcr from addition of Pertuzumab to standard Trastuzumab/Docetaxel 50 pcr, % ± 95% CI 40 30 20 29.0% 45.8% 6 10 0 TH THP HP TP Treatment 24.0% 16.8%

Residual disease after neoadjuvant therapy = micro-metastasis Micro-metastasis Residual disease Primary Tumor Bulk The molecular profile of cancer cells remaining after selection with neoadjuvant therapy may serve as a proxy for the alterations present in clinically-silent, drug-resistant CHEMO SURGERY micrometastases destined to recur C. Arteaga Recurrence

Nature Med 2012

Diverse oncogenic alterations in TNBCs after neoadjuvant chemotherapy High TP53 rates is universally of MYC and lost MCL1 PIK3CA amplifications mutations overlap BRCA1/2 with HER2 DNA gains repair aberrations Other diverse amplifications in RTKs and members of PIK3CA/AKT, MAPK and cell cycle pathways n=81 Balko and Arteaga, Unpublished

NeoSphere: Superior pcr from addition of Pertuzumab to standard Trastuzumab/Docetaxel 50 pcr, % ± 95% CI 40 30 20 29.0% 45.8% 6 10 0 TH THP HP TP Treatment 24.0% 16.8%

Study design San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 n=406 Placebo + trastuzumab PD Patients with HER2-positive MBC centrally confirmed (N = 808) 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab PD n=402 Docetaxel* 6 cycles recommended Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: Pertuzumab/Placebo: Trastuzumab: Docetaxel: 840 mg loading dose, 420 mg maintenance 8 mg/kg loading dose, 6 mg/kg maintenance 75 mg/m 2, escalating to 100 mg/m 2 if tolerated * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion MBC, metastatic breast cancer; PD, progressive disease Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 23

San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Primary endpoint: Independently assessed PFS n = 433 PFS events Progression-f free survival (%) 100 Ptz + T + D: median 18.5 months 90 80 70 60 50 40 30 20 10 0 n at risk Ptz + T + D Pla + T + D D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Pla + T + D: median 12.4 months 0 5 10 15 20 25 30 35 40 Time (months) 402 345 267 139 83 32 10 0 0 406 311 209 93 42 17 7 0 0 = 6.1 months HR = 0.62 95% CI 0.51 0.75 p<0.0001 Stratified by prior treatment status and region Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 24

Measuring response in trials of neoadjuvant endocrine therapy: Ki67 as surrogate biomarker A short course of TAM or ICI 182780 before surgery significantly reduced Ki67 in primary breast tumors The decrease of Ki67 after 14 days of TAM was related to subsequent response Clarke RB, Br J Cancer 1993, DeFriend DJ, Cancer Res 1994 Makris A, Breast Cancer Res Treat 1998

Ki67 changes with endocrine therapy in neoadjuvant can surrogate for results in adjuvant? NEOADJUVANT ADJUVANT Study No. of pts Ki67 changes Study No. of pts Results P024 185 LET > TAM BIG 1-98 8010 LET > TAM IMPACT 147 ANA > TAM ATAC 9366 ANA > TAM NEWEST 211 Fulvestrant 500mg > 250mg CONFIRM (MBC) 736 Fulvestrant 500mg > 250mg Z1031 177 ANA = EXE 175 ANA = LET MA27 7576 ANA = EXE FACE ~4000 ANA vs LET?

A reasonable major new role of neoadjuvant trials to be explored neoadjuvant sample Sample population with characteristics of interest random population A B General validity?? External validity as adjuvant? Measure pcr or other surrogate of benefit B > A

NOAH study design (n=115) H + AT q3w x 3 cycles H + T q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles HER2-positive LABC (IHC 3+ or FISH+) (n=113) AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles HER2-negative LABC (IHC 0/1+) (n=99) AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy a Surgery followed by radiotherapy a Surgery followed by radiotherapy a H continued q3w 19 crossed over to H to week 52 IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); q3w, every 3 weeks; T, paclitaxel (175 mg/m 2 ); q4w, every 4 weeks a Hormone receptor-positive patients will receive adjuvant tamoxifen

NOAH Neoadjuvant Trial: pcr rates with CT ± Trastuzumab Patients (%) 50 40 30 39% p=0.002 20 10 20% 0 With H Without H HER2 positive Gianni L et al, The Lancet - 2010

NOAH Neoadjuvant Trial: Concordance between improved pcr and EFS Probability, EFS 1.00 0.75 0.50 0.25 0.00 H + CT CT Patients 115 112 Events 36 52 HR a 0.56 0 6 12 18 24 30 36 42 Months Median follow-up is 3 years a Unadjusted for stratification variables: adjusted HR=0.55, p=0.0062 HR, hazard ratio; CI, confidence interval; CT, chemotherapy 95% CI 0.36-0.85 p a 0.006 Gianni L et al, The Lancet - 2010

A possible path to validation of the new role of neoadjuvant trials tandem studies Adjuvant Neoadjuvant Sample of neoadj random random A B A B compare DFS and OS Measure pcr or other surrogate of benefit

Amending the inherent weakness of the biomarkers quest The right population size must be driven by clinical endpoints AND by numerosity needed to derive robust evidence on biomarkers: Select a homogeneous patients population Apply informed decision on biologically relevant subsets (e.g. ER pos v. ER neg in the HER2-overexpressing population, or PI3K mutated v. wild type) Estimate the number of positive and negative events adequate for bioinformatic analysis Estimate the expected rate of events for each subset and calculate to enroll enough patients into the trial to feed the right number into the smallest subset of the control arm

Implications for the neoadjuvant approach Overall Design of next Michelangelo trial Biomarker driven Neoadjuvant marker ID Part 1 Will test in a neoadjuvant setting the presence of biomarkers associated with response/resistance and clinical/pathological endpoints Marker-driven Neoadjuvant Marker-driven Adjuvant Part 2 Will validate two concepts: a) applicability of markers and their clinical utility in the same neo-adjuvant setting b) more general applicability to the adjuvant scenario

Implication for future studies - II Conduct tandem neadjuvant and adjuvant trials The neoadjuvant studies should be: Randomized Sized to test for comparative pcr and comparative efficacy (Phase III not Phase II) Associated with 100% tumor and tissue banking before and after PST Sized to match the number of events required for the definition of markers of response/efficacy, not just the events for clinical comparison The companion adjuvant studies can be used to validate clinical and biomarker endpoints

Implication for future studies - III The right population size must be driven by clinical endpoints AND by numerosity needed to derive robust evidence on biomarkers: Select homogeneous patients population Apply informed decision on biologically relevant subsets (e.g. ER pos v. ER neg in the HER2-overexpressing population, or PI3K mutated v. wild type) Calculate the number of positive and negative events adequate for bioinformatic analysis Calculate the expected rate of events for each subset and enroll enough patients into the trial to feed the right number into the smallest subset of the control arm

Conclusions from NeoSphere biomarker analyses HER2 expression (H-score) associated with sensitivity to pertuzumab PI3K mutations in exon 9 linked to lack of sensitivity to HER2- directed Mab s Intrinsic differences between HER2+ tumors based on hormone receptor status No predictive role for truncated forms of the HER2 receptor including p95 HER2 So far none of the analyses provided clinically useful assays for patient and/or regimen selection in addition or alternative to the conventional assessment of HER2 by IHC or FISH 2

Outcomes of neoadjuvant chemotherapy in patients with unselected tumor characteristics unselected population failure pcr DFS benefit RD pcr Classification of cases with RD as non responders is an oversimplification and misleading

Standard approach and the challenge of Tumor Heterogeneity unselected population pcr HER2 20% ER-pos TN DFS benefit 75% Each subgroup (HER2+, TN and ER+) contributes differently to pcr and to DFS Predictors of pcr are not equivalent to prediction of DFS in patients unselected for tumor characteristics

In Praise of Tumor Heterogeneity The elusive link so far between pcr and benefit (DFS) is likely due to tumor heterogeneity The goal of predicting benefit cannot be based on average measures that will inevitably generate tools capable of average prognosis/prediction Primary systemic therapy should make use of heterogeneity of tumors and patients to meet the challenge of individualized medicine

The Evolving role of Neoadjuvant Systemic Therapy of Breast Cancer Control breast cancer locally (LABC and IBC) Increase rate of breast conserving surgery (BCS) Measure antitumor activity and rank therapies Predict benefit Substitute adjuvant trials for establishing new indications?

Implication for future studies - I pcr can be surrogate of DFS in the entire patient population Validation would promote PST as tool for the rapid test of new effective adjuvant therapies in selected molecular subsets of breast cancer How to validate the concept?